CN115073545A - Synthetic method of tildipirosin - Google Patents
Synthetic method of tildipirosin Download PDFInfo
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- CN115073545A CN115073545A CN202210944306.7A CN202210944306A CN115073545A CN 115073545 A CN115073545 A CN 115073545A CN 202210944306 A CN202210944306 A CN 202210944306A CN 115073545 A CN115073545 A CN 115073545A
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Abstract
The invention discloses a synthesis method of tildipirosin, belonging to the technical field of drug synthesis and comprising the following process steps: suspending the starting material tylosin phosphate in an organic solvent, adding piperidine for reaction under the action of a hydrochloric acid solution, and obtaining an intermediate through pH adjustment, extraction, drying and distillation; dissolving the intermediate in a polar solvent, adding piperidine for reaction under the action of a catalyst, and obtaining the tildipirosin through pH adjustment, extraction, distillation, crystal growth and suction filtration. The invention has the beneficial effects that: the method has the advantages that the operation is simple, the reaction period is short, the intermediate does not need to be dried, the intermediate can be directly put into the next reaction, column-passing purification is not needed, the preparation period is effectively shortened, the working efficiency is improved, and the purity of the Tildipirosin is high; greatly reduces the use of two solvents, greatly improves the purity and the safety, has less harmful substances in impurities, and is easy to refine and treat.
Description
The technical field is as follows:
the invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of tildipirosin.
Background art:
tildipirosin (Tildipirosin) is a new animal-dedicated macrolide semisynthetic antibiotic developed by England ® Wis company, is a derivative of tylosin, has very obvious therapeutic effect on respiratory diseases of cattle and pigs, has stronger drug effect than tylosin and tilmicosin, and has the advantages of animal-dedicated property, small dosage, one-time administration and whole-course treatment, ultra-long elimination half-life, high bioavailability, low residue and the like, and has the chemical name: 20, 23-dipiperidinyl-5-oxo-mycaminosyl-tylonolide, 3/8/2011, the veterinary drug Commission (CVMP) of the european union granted a market approval application for sterile injectable solutions of taxotere as a major ingredient from the intemet corporation, followed by successive approval for marketing in the european union countries.
The structural formula is as follows
For the synthesis of this compound, the methods reported so far mainly include the following:
patent CN 108033988A: the tylosin is subjected to amination reaction to convert aldehyde group at position 20 of the tylosin into piperidyl, hydrolysis reaction is carried out to remove glycosyl groups at positions 4 and 15, oxidation reaction and amination reaction are sequentially carried out to convert hydroxyl at position 23 into piperidyl, and finally the tylosin is obtained. The method has the disadvantages of complicated operation, multiple steps, low product yield, low purity of the tildipirosin which is only 97 percent and low product purity.
Patent WO2008012343 is a synthesis method reported by the original research company, tylosin is used as a raw material, and the tylosin is subjected to amination reduction, high-concentration strong acid hydrolysis, iodide activation of 23 sites, and amination reaction again to obtain the tildipirosin. The method has the advantages of more byproducts, and the total yield of the product is only 12.2 percent, which is not suitable for industrial production.
Patent CN102863487 discloses a new preparation method, which takes tylosin tartrate as a starting material, and obtains 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide through hydrolysis, amination, iodination and secondary amination. The method still needs hydrolysis, amination, iodination and secondary amination to obtain the tildipirosin bulk drug, and has the disadvantages of complex steps, low yield, complex post-treatment and high three wastes.
Patent US6514946 reports a method for obtaining tylonolide by reflux reaction of 20, 23-diiodo-5-O-mycaminosyl-tylonolide as a raw material with piperidine in acetonitrile, and subjecting the reaction liquid to column chromatography, wherein the method is not easy to obtain 20, 23-diiodo-5-O-mycaminosyl-tylonolide and the column chromatography is not beneficial to industrial popularization.
Patent CN201410108841 reports a method for preparing tildipine by using tylosin tartrate as a raw material, through ammoniation, high-concentration strong acid hydrolysis, sodium hypochlorite oxidation and piperidine ammoniation, the method is a method for preparing tildipine by reacting 23-position hydroxyl to generate aldehyde group, the reaction is a selective oxidation reaction, people are not easy to strictly control the reaction process at the stage of generating aldehyde group, and aldehyde is generally unstable, so the reaction process is difficult to accurately control. The reaction conditions are harsh, the process route is difficult to control, and the yield is not high.
Patent CN102863487A reports a method of using tylosin tartrate as raw material, which comprises the steps of firstly carrying out hydrolysis reaction on the raw material by using hydrobromic acid, introducing piperidine group, preparing 20-piperidyl-23-hydroxy-5-O-mycaminosyl-tylonolide, then carrying out iodination reaction on 23 position, and finally introducing piperidine group on 23 position. According to the method, the iodination reaction needs triphenylphosphine and elemental iodine, and the triphenylphosphine byproduct has high toxicity and is easy to pollute the environment; the price of the elementary iodine is higher, the unit price of the product is improved, and the market competition is not facilitated.
CN104892704 reports: after the tylosin tartrate is hydrolyzed, the 23-position hydroxyl is oxidized into aldehyde group by TEMPO, and then the tylosin is obtained through reductive amination reaction. TEMPO has strong oxidizability, which easily causes hydroxyl groups at other positions to be oxidized, so that the purity of the product is very low, and industrial mass production is uncontrollable.
In summary, the following steps: the above methods all have more or less problems: some synthesis steps are multiple, and the product yield is low; some catalysts have high toxicity and high price and are not feasible economically; some by-products are high, so that the product purity is low; some industrial large-scale production is difficult to control and the productivity is low. Therefore, the development of an environment-friendly, economically feasible and high-purity synthesis method of tildipirosin is a hot spot of current research.
The invention content is as follows:
in order to solve the problems and overcome the defects of the prior art, the invention provides a synthesis method of tildipirosin, which reduces the use of two solvents, does not generate harmful gas, has mild reaction temperature and conditions, is easy to control, reduces the probability of danger generation, and has the advantages of low cost, environmental protection, high product yield and high purity.
The specific technical scheme for solving the technical problems comprises the following steps: a synthetic method of tildipirosin comprises the following process steps:
step (I): suspending the starting material tylosin phosphate in an organic solvent, adding piperidine for reaction under the action of a hydrochloric acid solution, and obtaining an intermediate through pH adjustment, extraction, drying and distillation;
step (II): dissolving the intermediate in a polar solvent, adding piperidine for reaction under the action of a catalyst, and obtaining the tildipirosin through pH adjustment, extraction, distillation, crystal growth and suction filtration.
Further, the catalyst is H + -montmorillonite.
Further, the step (i) comprises:
(1) suspending the starting material tylosin phosphate in an organic solvent for later use: the organic solvent comprises ethyl acetate or butyl acetate or diethyl ether, and the mass volume ratio of the tylosin phosphate to the organic solvent is 1: 5-20;
(2) adding a hydrochloric acid solution into the tylosin phosphate suspension; the molar concentration of the hydrochloric acid solution is 1.0-1.8 mol/L; the mass volume ratio of the tylosin phosphate to the hydrochloric acid solution is 1: 2.0-5.0;
(3) controlling the reaction temperature to be 50-77 ℃, and adding piperidine into the reaction liquid for 5-10 hours; the mass ratio of the tylosin phosphate to the piperidine is 1: 0.15-0.25;
(4) after the reaction is finished, adding water into the reaction solution, adjusting the pH to 6.5-7.5 by using alkali liquor, performing layered extraction, taking an organic phase, adding anhydrous sodium sulfate, drying, performing suction filtration, and distilling to obtain an intermediate; the alkali liquor comprises sodium carbonate or potassium carbonate or ammonia water or triethylamine.
Further, the step (II) comprises the following steps:
(1) adding the intermediate into a polar solvent for dissolving for later use, wherein the polar solvent comprises sulfolane, dimethyl sulfoxide and 1, 4-dioxane, and the mass volume ratio of the intermediate to the polar solvent is 1: 6-12;
(2) adding a catalyst H & lt + & gt-montmorillonite into the intermediate dissolving solution; the mass ratio of the intermediate to the H + -montmorillonite is 1: 0.2-0.5;
(3) controlling the reaction temperature to be 60-90 ℃, and adding piperidine into the reaction liquid for 6-8 hours; the mass ratio of the intermediate to the piperidine is 1: 0.10-0.25;
(4) after the reaction is finished, adding water and ethyl acetate into the reaction solution, adjusting the pH to 8.0-9.5 by using alkali liquor, performing layered extraction, taking an organic phase, adding anhydrous sodium sulfate for drying, performing suction filtration, then distilling, cooling for growing crystals, and performing suction filtration and drying to obtain tildipirosin;
the alkali liquor comprises sodium carbonate or potassium carbonate or ammonia water or triethylamine; the crystal growing temperature is-5 ℃.
Further, in the step (I), the pH value is adjusted, and the temperature of extraction and drying is controlled to be 20-30 ℃.
Further, in the step (II), the pH value is adjusted, and the temperature is controlled to be 25-35 ℃ for extraction and drying.
Further, the intermediate is 23-hydroxy-20-piperidinyl-5-oxy-mycaminosyl-tylonolide.
The invention has the beneficial effects that:
the method for synthesizing the tildipirosin is simple to operate and short in reaction period, the intermediate does not need to be dried, the intermediate can be directly put into the next reaction, column purification is not needed, the preparation period is effectively shortened, the working efficiency is improved, and the purity of the tildipirosin is over 98.5%;
the use of a second solvent is greatly reduced, the purity and the safety are greatly improved, and harmful substances in impurities are less and are easy to refine; has the characteristics of less pollution, environmental protection, simple process, mild condition, low cost, high product purity and the like, and is very suitable for industrial mass production.
Description of the drawings:
FIG. 1 is a schematic diagram of the present invention;
the specific implementation mode is as follows:
in the description of the invention, specific details are given only to enable a full understanding of the embodiments of the invention, but it should be understood by those skilled in the art that the invention is not limited to these details for the implementation. In other instances, well-known structures and functions have not been described or shown in detail to avoid obscuring the points of the embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in a specific case to those of ordinary skill in the art.
The specific implementation mode of the invention is as follows:
in order to better understand the present invention, the specific embodiments are specifically illustrated, it is emphasized that the effects of the embodiments are not substantially different from the various embodiments within the scope of the present invention, including the respective reagents and the content ratios of the reagents, which can achieve the described effects of the present invention and solve the above problems, and other combinations are not described herein;
example (1):
taking 101.41g (0.1mol) of tylosin phosphate in a three-neck flask, taking 650ml of organic solvent ethyl acetate as a reaction solvent, adding 320ml of 1.6mol/L hydrochloric acid solution and 17.03g (0.2mol) of piperidine under the condition of stirring, heating to 65 ℃, and reacting for 8 hours in a timed manner; after the reaction is finished, adding 100ml of water into the reaction solution, and cooling to 20-30 ℃; regulating the pH value to 6.5-7.5 by using a saturated sodium carbonate solution, stirring for about 10min, layering, removing a water phase, and taking an organic phase; adding anhydrous sodium sulfate, drying for about 30min, vacuum filtering to obtain mother liquor, and distilling until liquid drops are not dropped out basically to obtain 54.8g of intermediate.
Dissolving the intermediate in 900ml of polar solvent 1, 4-dioxane, adding 30.42g of catalyst H + -montmorillonite and 12.77g of piperidine (0.15mol), heating to 80 ℃, timing and reacting for 7H; after the reaction is finished, adding 300ml of water and 1.5L of ethyl acetate serving as an extractant into the reaction solution, adjusting the pH to 8.0-9.5 by using a saturated sodium carbonate solution, performing layered extraction, taking an organic phase, adding anhydrous sodium sulfate for drying, performing suction filtration, distilling until the volume of the organic phase is about 200ml, cooling to 0 ℃ for crystal growth for about 12 hours, performing suction filtration, washing with ethyl acetate, and drying to obtain 49.62g of tildipirosin.
Example (2):
30.42g (0.03mol) of tylosin phosphate is taken in a three-neck flask, and 96ml of 1.3mol/L hydrochloric acid solution and 5.11g (0.06mol) of piperidine are added under the condition of stirring by taking 200ml of organic solvent butyl acetate as a reaction solvent, and the temperature is raised to 65 ℃ for reaction for 8 hours. After the reaction is finished, adding 30ml of water into the reaction solution, and cooling to 20-30 ℃. Regulating the pH value to 6.5-7.5 by using a saturated sodium carbonate solution, stirring for about 10min, layering, discarding the water phase, taking the organic phase, adding anhydrous sodium sulfate, drying for about 30min, performing suction filtration to obtain a suction filtration mother liquor, and distilling until liquid drops do not drip out basically to obtain an intermediate 16.4 g;
the intermediate was dissolved in 270ml of 1, 4-dioxane, a polar solvent and 10.14g of catalyst H + -montmorillonite and 4.26g of piperidine (0.045mol) were added. The temperature is increased to 80 ℃ and the reaction is carried out for 7 h. And after the reaction is finished, adding 100ml of water and 500ml of ethyl acetate serving as an extractant into the reaction solution, adjusting the pH to 8.0-9.5 by using a saturated sodium carbonate solution, performing layered extraction, and taking an organic phase. Adding anhydrous sodium sulfate, drying, vacuum filtering, distilling to obtain residual volume of 60ml, cooling to 0 deg.C, growing crystal for 12 hr, vacuum filtering, washing with ethyl acetate, and drying to obtain 14.32g of Tildipirosin;
example (3):
50.71g (0.05mol) of tylosin phosphate is taken in a three-neck flask, 400ml of organic solvent ethyl ether is taken as a reaction solvent, 175ml of 1.4mol/L hydrochloric acid solution and 8.52g (0.1mol) of piperidine are added under the condition of stirring, the temperature is raised to 65 ℃, and the reaction is timed for 8 hours. After the reaction is finished, adding 50ml of water into the reaction solution, and cooling to 20-30 ℃. And (3) regulating the pH to 6.5-7.5 by using a saturated sodium carbonate solution, stirring for about 10min, layering, removing the water phase, and taking an organic phase. Adding anhydrous sodium sulfate, drying for about 30min, vacuum filtering to obtain mother liquor, and distilling until liquid drops are not dropped out basically to obtain intermediate 26.21 g;
the intermediate was dissolved in 450ml of 1, 4-dioxane and 15.21g of the catalyst H + -montmorillonite and 6.39g of piperidine (0.075mol) were added. The temperature is increased to 80 ℃ and the reaction is carried out for 7 h. After the reaction is finished, adding 150ml of water and 750ml of ethyl acetate serving as an extractant into the reaction solution, adjusting the pH to 8.0-9.5 by using a saturated sodium carbonate solution, performing layered extraction, and taking an organic phase. Adding anhydrous sodium sulfate, drying, vacuum filtering, distilling to obtain residual volume of about 100ml, cooling to 0 deg.C, growing crystal for about 12h, vacuum filtering, washing with ethyl acetate, and drying to obtain 24.28g of Tildipirosin;
example (4):
60.84g (0.06mol) of tylosin phosphate is taken to be put in a three-neck flask, and 200ml of 1.3mol/L hydrochloric acid solution and 10.22g (0.12mol) of piperidine are added under the condition of stirring by taking 400ml of organic solvent ethyl acetate as a reaction solvent, and the temperature is raised to 65 ℃ for reaction for 8 hours. After the reaction is finished, adding 30ml of water into the reaction solution, and cooling to 20-30 ℃. And (3) regulating the pH to 6.5-7.5 by using a saturated sodium carbonate solution, stirring for about 10min, layering, removing the water phase, and taking an organic phase. Adding anhydrous sodium sulfate, drying for about 30min, vacuum filtering to obtain mother liquor, and distilling until liquid drops are not dropped out basically to obtain 33.36g of intermediate;
the intermediate was dissolved in 350ml of dimethyl sulfoxide and 20.28g of the catalyst H + -montmorillonite and 8.52g of piperidine (0.09mol) were added. The temperature is increased to 80 ℃ and the reaction is carried out for 7 h. After the reaction is finished, adding 200ml of water and 1000ml of ethyl acetate serving as an extractant into the reaction solution, adjusting the pH to 8.0-9.5 by using a saturated sodium carbonate solution, performing layered extraction, and taking an organic phase. Adding anhydrous sodium sulfate, drying, vacuum filtering, distilling to obtain residual volume of about 120ml, cooling to 0 deg.C, growing crystal for about 12h, vacuum filtering, washing with ethyl acetate, and drying to obtain 29.10g of Tildipirosin;
example (5):
91.26g (0.09mol) of tylosin phosphate is taken in a three-neck flask, and 300ml of 1.3mol/L hydrochloric acid solution and 15.33g (0.18mol) of piperidine are added into a reaction solvent of 600ml of organic solvent ethyl acetate under the condition of stirring, and the temperature is raised to 65 ℃ for reaction for 8 hours. After the reaction is finished, adding 30ml of water into the reaction solution, and cooling to 20-30 ℃. And (3) regulating the pH to 6.5-7.5 by using a saturated sodium carbonate solution, stirring for about 10min, layering, removing the water phase, and taking an organic phase. Adding anhydrous sodium sulfate, drying for about 30min, vacuum filtering to obtain mother liquor, and distilling until liquid drops are not dropped out basically to obtain 47.52g of intermediate;
the intermediate was dissolved in 270ml of sulfolane and 36.50g of the catalyst H + -montmorillonite and 12.78g of piperidine (0.135mol) were added. The temperature is increased to 80 ℃ and the reaction is carried out for 7 h. After the reaction is finished, adding 300ml of water and 1500ml of ethyl acetate serving as an extracting agent into the reaction solution, adjusting the pH to 8.0-9.5 by using a saturated sodium carbonate solution, performing layered extraction, and taking an organic phase. Adding anhydrous sodium sulfate, drying, vacuum filtering, distilling to obtain residual 200ml, cooling to 0 deg.C, growing crystal for 12 hr, vacuum filtering, washing with ethyl acetate, and drying to obtain 42.99g of Tildipirosin;
in order to more intuitively show the process advantages of the invention, the synthetic method of the tildipirosin is compared with the alternative method adopted by the same process,
comparative example one:
the preparation method is the same as the embodiment except that: in the preparation process of the comparative example, the catalyst which is not added is H + -montmorillonite;
and the detection is carried out according to a detection method about Tildipirosin in Chinese pharmacopoeia, and the test result is as follows:
table 1: data comparing properties of different example and comparative example products
| Molar yield of intermediate | Tildipirosin molar yield | Purity of Tildipirosin | Class II solvents | |
| Example (1) | 82.04％ | 82.41％ | 98.8％ | Not detected out |
| Example (2) | 81.84％ | 79.47％ | 98.9％ | Not detected out |
| Example (3) | 78.47％ | 84.31％ | 99.1％ | Undetected |
| Example (4) | 83.23％ | 79.38％ | 98.7％ | Not detected out |
| Example (5) | 79.04％ | 82.32％ | 99.2％ | Not detected out |
| COMPARATIVE EXAMPLE (1) | 80.05％ | 12.15％ | 73.7％ | Not detected out |
From the above table, it can be seen that:
comparing the data according to examples 1-5 with comparative example 1: the molar yield of 23-hydroxy-20-piperidinyl-5-oxo-mycaminosyl-tylonolide as an intermediate has little influence, while the molar yield and purity of tylonolide have a greater influence;
the reason for this is probably that no catalyst is added, and the intermediate 23-hydroxy-20-piperidyl-5-oxo-mycaminosyl-tylonolide cannot react well with piperidine, and then Tildipirosin with higher purity and better yield is obtained through pH regulation, extraction, distillation, crystal growing and suction filtration.
Most importantly: compared with a plurality of comparison documents disclosed in the technical background, the method for synthesizing the tildipirosin has the advantages of simple operation, short reaction period, no need of drying the intermediate, direct reaction in the next step, no need of column purification, effective shortening of the preparation period, improvement of the working efficiency and purity of the tildipirosin of more than 98.5%;
meanwhile, the method for synthesizing the tildipirosin can greatly reduce the use of two solvents, only needs to introduce a small amount of solvents when an intermediate is dissolved, and greatly reduces the influence of the two solvents on the environment; after the subsequent steps of the invention are carried out, the residue of the second class solvent meets the requirements of national formulary, the purity and the safety are greatly improved, the harmful substances are less, and the refining treatment is easy; has the characteristics of less pollution, environmental protection, simple process, mild condition, low cost, high product purity and the like, and is very suitable for industrial mass production.
Claims (7)
1. A synthetic method of tildipirosin is characterized by comprising the following steps: the method comprises the following process steps:
step (I): suspending the starting material tylosin phosphate in an organic solvent, adding piperidine for reaction under the action of a hydrochloric acid solution, and obtaining an intermediate through pH regulation, extraction, drying and distillation;
step (II): dissolving the intermediate in a polar solvent, adding piperidine for reaction under the action of a catalyst, and obtaining the tildipirosin through pH adjustment, extraction, distillation, crystal growth and suction filtration.
2. The process for the preparation of tildipirosin according to claim 1, wherein the catalyst is H + -montmorillonite.
3. The process for preparing tildipirosin according to claim 1, wherein the step (i) comprises:
(1) suspending the starting material tylosin phosphate in an organic solvent for later use; the organic solvent comprises ethyl acetate or butyl acetate or diethyl ether, and the mass volume ratio of the tylosin phosphate to the organic solvent is 1: 5-20;
(2) adding a hydrochloric acid solution into the tylosin phosphate suspension; the molar concentration of the hydrochloric acid solution is 1.0-1.8 mol/L; the mass volume ratio of the tylosin phosphate to the hydrochloric acid solution is 1: 2.0-5.0;
(3) controlling the reaction temperature to be 50-77 ℃, and adding piperidine into the reaction liquid for 5-10 h; the mass ratio of the tylosin phosphate to the piperidine is 1: 0.15-0.25;
(4) after the reaction is finished, adding water into the reaction solution, adjusting the pH to 6.5-7.5 by using alkali liquor, performing layered extraction, taking an organic phase, adding anhydrous sodium sulfate, drying, performing suction filtration, and distilling to obtain an intermediate; the alkali liquor comprises sodium carbonate or potassium carbonate or ammonia water or triethylamine.
4. Process for the preparation of tildipirosin according to claim 2, characterized in that step (II) comprises:
(1) adding the intermediate into a polar solvent for dissolving for later use, wherein the polar solvent comprises sulfolane, dimethyl sulfoxide or 1, 4-dioxane, and the mass volume ratio of the intermediate to the polar solvent is 1: 6-12;
(2) adding a catalyst H & lt + & gt-montmorillonite into the intermediate dissolving solution; the mass ratio of the intermediate to the H + -montmorillonite is 1: 0.2-0.5;
(3) controlling the reaction temperature to be 60-90 ℃, and adding piperidine into the reaction liquid for 6-8 hours; the mass ratio of the intermediate to the piperidine is 1: 0.10-0.25;
(4) after the reaction is finished, adding water and ethyl acetate into the reaction solution, adjusting the pH to 8.0-9.5 by using alkali liquor, performing layered extraction, taking an organic phase, adding anhydrous sodium sulfate for drying, performing suction filtration, then distilling, cooling for growing crystals, and performing suction filtration and drying to obtain tildipirosin;
the alkali liquor comprises sodium carbonate or potassium carbonate or ammonia water or triethylamine; the temperature of growing the crystal is-5 to 5 ℃.
5. The process for the preparation of tildipirosin according to claim 3, wherein the temperature for the pH adjustment, extraction and drying in step (I) is controlled to 20 to 30 ℃.
6. The process for preparing tildipirosin according to claim 4, wherein the temperature of the pH adjustment, extraction and drying in step (II) is controlled to be 25-35 ℃.
7. The process for the preparation of tildipirosin according to any one of claims 1 to 6, characterized in that the intermediate is 23-hydroxy-20-piperidinyl-5-oxy-mycaminosyl-tylonolide.
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| CN112679570A (en) * | 2020-12-25 | 2021-04-20 | 武汉回盛生物科技股份有限公司 | Synthesis and purification method of tildipirosin |
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